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Protein networks for nicotinic acetylcholine receptors

Institution: University of California, San Diego
Investigator(s): David Gomez Varela, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18FT-0050 Award: $134,878
Subject Area: Nicotine Dependence
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Cigarette smoking delivers nicotine to the brain where it binds to specific proteins in the membrane of cells. These proteins are called nicotinic acetylcholine receptors (nAChRs), and their activation by nicotine is the first molecular step in the addiction process. Normally these receptors are activated by a chemical in the brain called acetylcholine. Activation of the receptors sets in motion a chain of events in the cell that depends on the other proteins likely to be tethered in close proximity to the receptor. Depending on the composition of those partners, receptor activation can have a variety of effects. In fact, activation of nAChRs normally contributes to numerous higher order brain functions and behaviors. Aberrant nAChR activation has been implicated in a number of diseases including Alzheimer’s, Parkinson’s, and schizophrenia, in addition to nicotine addiction.

We have obtained preliminary results revealing the identity of three proteins that are candidate partners for a major nAChR in brain. In addition to its abundance, the nAChR subtype involved is interesting because it is exceptional at mobilizing calcium to set in motion numerous events in brain cells and in the circuits they comprise. These three candidates partners are (1) PSD-95, a protein that can act as a scaffold to assemble components in cells, (2) PMCA2 which acts as a calcium pump to remove excess calcium from cells, and (3) NCAM2 which is a novel member of a family of proteins that connect cells together (cell adhesion molecules). Given the known properties of these proteins and given our preliminary results suggesting they are associated with the same nAChR, the three candidates may work together to dictate the outcome of receptor activation.

Three Specific Aims are proposed here. The First Aim is designed to understand how these three proteins interact with nAChRs, specifically testing whether PSD-95 controls the location of the receptor on the cell surface because this can be critical in determining when the receptor is activated. The Second Aim uses functional assays to study how interactions of the three proteins with the receptor and with each other determine the consequences of nAChR activation. The Third Aim determines how NCAM2 affects nAChR location, nAChR linkage to other components both inside the cell and outside the cell, and nAChR function.

The information obtained here will provide new insight into molecular mechanisms that determine the consequences of nicotinic stimulation. These mechanisms represent targets that are vulnerable to tobacco-derived nicotine. Understanding their interactions and physiological consequences will not only increase our knowledge of nicotinic physiology in brain, but it will also underscore the dangers of nicotine consumption and may suggest therapeutic strategies that can be tested.

Lateral Mobility of Nicotinic Acetylcholine Receptors on Neurons is Determined by Receptor Composition, Local Domain, and Cell Type
Periodical: Journal of Neuroscience Index Medicus:
Authors: Caterina C. Fernandes, Darwin K. Berg and David Gomez-Varela ART
Yr: 2010 Vol: 30 Nbr: Abs: Pg: 8841-51

Pmca2 via Psd-95 controls calcium signaling by a7-containing nicotinic receptors on aspiny interneurons
Periodical: Journal of Neuroscience Index Medicus:
Authors: David Gomez-Varela, Manuela Schmidt, Jeff Schoelermann, Eric Peters and Darwin K. Berg ART
Yr: Vol: Nbr: Abs: Pg: